https://indigonaturals.net/blogs/news.atomindigonaturals.net - Blog2019-05-23T14:45:00-07:00indigonaturals.nethttps://indigonaturals.net/blogs/news/what-research-says-about-weed-or-thc-versus-cbd-for-anxiety2019-05-23T14:45:00-07:002019-05-23T16:52:44-07:00What Research Says About Weed or THC versus CBD for AnxietyIndigo Naturals
What Research Says About Weed or THC versus CBD for Anxiety

Interesting studies point to a very different effect on anxiety between weed and CBD

Research is actually there which looks at the difference between weed or THC and CBD's effect on anxiety.

There are numerous studies that dive all the way down to what genes are turned on and off with either.

The results are pretty clear when comparing the two.

Maybe more importantly, new research is pointing to how THC might structurally change the brain to make it more prone to future anxiety and depression.

We're not anti-weed but people need to make informed decisions.

If anything, CBD might help to protect from these changes and even repair them!

Let's look at new research on exact effects on the anxiety circuit in the brain.

Interestingly, many people describe a calming sensation from cannabis or weed.

How does that fit with the research?

We'll cover these topics:

Research on weed and THC versus CBD for anxiety

The relationship between THC and CBD for anxiety

Long term changes from THC to anxiety circuit

Dosage effects of THC and CBD for anxiety

Best type of CBD for anxiety (i.e. histamine or allergic response to cannabis)

Let's get started.

Research on weed and THC versus CBD for anxiety

We're going to use weed and THC interchangeably.

Why?

The two most prominent cannabinoids in cannabis or weed are:

THC

CBD

By far!

The other cannabinoids (CBC, CBG, CBN, etc) are generally found in very small, almost negligible levels.

If you look at any purported "full spectrum" CBD 3rd party testing, you'll see parts per million usually for these chemicals.

That's just the way the plant is.

Yes, that is becoming more skewed with each passing year.

Meaning...there are new strains with much higher levels of THC for more recreational effects.

This is generally at the expense of CBD in the plant...an unfortunate result in terms of anxiety as we'll see below.

We'll get into why this matters below as their relationship is pretty interesting.

The psychoactive effects of weed or cannabis is primarily due to its THC level.

What does research show in terms of THC and anxiety?

There are three aspects to look at:

THC's and CBD's direct effects on the anxiety circuit

Allergic reactions to THC for 24-36% of the population

Other contaminants, pesticides, heavy metals, etc in weed or cannabis

Let's start with THC's direct effect on anxiety.

It's really tough to find THC by itself since effects of weed or cannabis will also include CBD which has a known anti-anxiety effect by itself (see CBD and anxiety here).

Most of the studies are on cannabis.

The effects of THC via weed on the anxiety circuit appear to be biphasic depending on dose.

The majority of users report that consumption of modest amounts of cannabis and CB1 receptor agonists results in euphoria, relaxation, heightened perception, sociability and creativity, moderate to high doses have been reported to elicit phobia, agitation, panic, dysphoria, psychotic manifestations and cognitive impairments

Lower doses of cannabis (THC by proxy) may have a calming effect while higher levels can have the opposite effect.

7.5mg THC significantly reduced self-reported subjective distress after the TSST and attenuated post-task appraisals of the TSST as threatening and challenging. By contrast, 12.5mg THC increased negative mood overall i.e., both before and throughout the tasks,

To get to the heart of THC's effects on anxiety, let's look at some well-known components:

THC versus CBD and the Amygdala - seat of emotional and fear response

THC versus CBD and the Prefrontal Cortex - rational part of brain that offsets fear response

THC versus CBD and the Hippocampus - a modulator of fear signals

THC versus CBD and the Uncinate Fasciculus - communication link between the two tied to anxiety

THC versus CBD and GABA levels - the "brake" in the brain tied to calming sensation

One at a time!

We'll see that THC has a blanket effect across most areas of the brain since CB1 receptors (our natural endocannabinoid receptors) are found almost everywhere in the brain.CBD affect CB2 receptors more so its effect is different from THC.

Let's start in the fear center.

THC or Cannabis versus CBD and the Amygdala

This is big and partially depends on age.

One study looked at health adult subjects and studied the effects of THC by itself on the Amygdala:

Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear.

The real interesting research on this area deals with cannabis consumption during adolescents.

It was found that just 1-2 uses of cannabis at age 14-15 could thicken the amygdala and make a person more prone to anxiety later in life.

More Amygdala signaling...more potential anxiety.

The biggest differences in gray matter were in the amygdala, which is involved in fear and other emotion-related processes, and in the hippocampus, involved in memory development and spatial abilities.

This is frightening. We'll look at ways to try and offset this effect later.

This now sheds light on past information:

Weekly or more frequent cannabis use in teenagers predicted an approximately twofold increase in risk for later depression and anxiety (1.9, 1.1 to 3.3) after adjustment for potential baseline confounders. In contrast, depression and anxiety in teenagers predicted neither later weekly nor daily cannabis use.

Let's also bring up the middleman in this circuit...the anterior cingulate cortex (ACC).

The ACC is a relay messenger between the two big players in the anxiety circuit...the Amygdala (fear) and the Prefrontal Cortex (reason).

What does CBD do there?

functional neuroimaging (fMRI) study found evidence for attenuation of the blood-oxygen level dependent (BOLD) signal in the amygdala and the posterior and ACC in response to the presentation of fearful faces, combined with a reduction in subjective anxiety

The firing of the anxiety cells sends messages to other parts of the brain that turn on anxious behaviors; in mice, those include avoiding the dangerous area or fleeing to a safe zone.

Think of these cells as the instigator or "on switch" for anxiety response.

As the researchers put it:

Though many other cells in the brain have been identified as playing a role in anxiety, the cells found in this study are the first known to represent the state of anxiety, regardless of the type of environment that provokes the emotion.

Clearly, proper function of the hippocampus is part of the anxiety loop.

If you want a powerful example from this experiment:

By turning the anxiety cells off and on using a technique called optogenetics that allows scientists to control the activity of neurons using beams of light, the researchers found that the anxiety cells control anxiety behaviors

The could literally switch anxiety behavior on and off with these cells!

CBD induced a substantial increase in net neurogenesis by a CB1 receptor-dependent mechanism

These data are supported by evidence that repeated administration of CBD to wild-type mice increases hippocampal NPC proliferation via CB1 receptors, which may underlie the anxiolytic effect of CBD in chronically stressed animals

"Anxiolytic" just means anti-anxiety.

This is important because it goes towards a long term addressing of the anxiety circuit.

In a study, they gave CBD to one set of participants and a placebo to another set.

They then administered high levels of THC (enough to provoke a psychotic reaction):

pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Δ-9-THC.

The "stress hormone" cortisol is believed to create a domino effect that hardwires pathways between the hippocampus and amygdala in a way that might create a vicious cycle by creating a brain that becomes predisposed to be in a constant state of fight-or-flight.

Deficiency of CB1 receptor signaling is associated with anhedonia, anxiety, and persistence of negative memories.

When we have acute stress (which can actually be good for us...a test, exercise, etc), the endocannabinoid system works to counter the spike in cortisol in order to bring the system back to balance.

It's chronic cortisol and stress that eventually exhausts this system:

Chronic variable stress exposure reduces endocannabinoid-CB1 receptor signaling and it is hypothesized that the resultant deficiency in endocannabinoid signaling contributes to the negative consequences of chronic stress.

This is critical.

Basically, the negatives of cortisol and stress (anxiety being one of them) are a result of our endocannabinoid system not being able to respond as well.

We see this throughout the body such as with insulin resistant diabetes.

There's an interesting player in this whole pathway.

Anandamide.

Anandamide (AEA) is our naturally created endocannabinoid with primary residence in the brain and nervous system.

It's called the "bliss" molecule and named after the Hindu Goddess of bliss, Anand.

We've covered it in detail as its effects are generally "anti-anxiety".

Some interesting research has come out in terms of cortisol and anxiety.

Think of anandamide as a correcting mechanism...a buffer from stress-induced spikes in cortisol.

It may be the "fuel" that runs out from chronic stress and cortisol:

Interestingly, stress induction, through the use of personally relevant stress-related imagery, has been found to result in a progressive decline in the circulating levels of AEA

A quick note...cortisol in integral to our sleep cycle. It wakes you up and cycles with highest levels in the morning (to wake us up), decreases at night (hopefully), with a bump around 4am (hmm hmm...anyone else with a restroom break around then??).

Too little cortisol in the morning and too much at night is a sign of cortisol dysfunction and sleep issues.

Another study looked at this aspect of CBD's effect on cortisol:

Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time.

cannabidiol (CBD) treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement.

In this case, it's supporting the natural system we have to mediate the effects of stress in the brain.

Remember that if left unchecked, these effects can actually change brain structure with results being future anxiety (and other issues)..

That's where neurogenesis comes into play.

Building new pathways or repairing existing ones which have been damaged by elevated cortisol levels.

We couldn't sum it up better than researchers did here:

More recently, a studied conducted with transgenic mice (GFAP-TK mice) showed that the anxiolytic effect of chronic CBD administration (14 days) in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signaling

Basically, they're saying the anti-anxiety (anxiolytic) effect of CBD following stress was from neurogenesis in the hippocampus.

Recent research is showing that SSRI's, commonly prescribed for anxiety, may also have their effect via this mechanism.

Moreover, CB1 knockout mice displayed functional impairment of 5-HT1A and 5-HT2A/C receptor-mediated neurotransmission in the hippocampus [117] while a loss of antidepressants behavioral effects was described after genetic blocked of CB1 receptors [118].

Again, everything we do at IndigoNaturals is based on research in order to provide the best response to CBD.

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https://indigonaturals.net/blogs/news/cbd-medication-exercise-and-neurogenesis-for-anxiety-the-road-to-long-term-change2019-05-16T23:03:00-07:002019-05-23T19:24:11-07:00CBD, Medication, Exercise and Neurogenesis for Anxiety - A path to long term changeIndigo Naturals
CBD, medication, exercise and neurogenesis for anxiety - the road to long term change

Learn how CBD, meditation, and exercise can repair brains with neurogenesis for anxiety and more

We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress

This may be why SSRI's can take 2 weeks plus to have an impact. They actually increase anxiety and depression in the first two weeks.

Synaptogenesis is just a cool way to say that the brain is learning new tricks...building new pathways.

The prefrontal cortex is part of our anxiety circuit (the rational brain that tells the amygdala to calm down).

Of course, the hippocampus was also in play:

The acute antidepressant effects (30 min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC)

It goes beyond that though.

Remember all those various slights to our anxiety pathway...injuries, illness, and traumas?

Glucocorticoids (GCs) influence neuronal development and functions, as well as BDNF.

reduced levels in both BDNF expression and hippocampal neurogenesis occurs along with depressive behaviors, suggesting that a changed status of the BDNF/TrkB system and reduced neurogenesis are associated with depressive symptoms.

So CBD is part of our arsenal in repairing the brain for anxiety (and in general).

Next up...meditation.

Does Meditation help with neurogenesis for anxiety?

In our 100's of hours of research, we were surprised when we came across multiple studies on mindful meditation and brain plasticity and mass across a range of areas.

Specifically, we were looking at how THC negatively impacts a key communication link in brain which affects anxiety.

The uncinate fasciculus. (say that 5 times fast).

So called "white matter", this brain area connects the prefrontal cortex with the amygdala (THE anxiety circuit essentially).

THC has been shown to shrink volume in this area if used chronically or when a person is in adolescents (see teenage anxiety and CBD).

Can we reverse or protect against this?

CBD had effects there as well via an interesting mechanism (see here) but mindful medication popped up.

In a big way!

Specifically…

The present study revealed a significant increase in fractional anisotropy in the right UNC following MBSR, and no significant change in the control group.

To translate, the researchers found increase mass in this particular link after mindful meditation.

It corresponded with reduced stress and anxiety responses.

That's one area.

This study went even further and found:

Regions within the brainstem were found to increase in gray matter concentration over the eight weeks. These regions appear to include the area of the locus coeruleus, nucleus raphe pontis, pontine tegmentum, and the sensory trigeminal nucleus

Considerable evidence exists that the neurons of this system are important in a variety of cognitive, affective, and other behavioral functions, as well as associated clinical dysfunctions (e.g., depression, anxiety, sleep, and circadian disorders; for discussion, see (Aston-Jones, 2002). It is also one of the primary sites for the mediation of the stress response as well as a site of action of antidepressant drugs

Just an FYI, the "raphe" area is where serotonin is made!

Did you also catch that last part about antidepressant drugs? (hint hint neurogenesis may be the benefit there).

It's a very interesting review of many different studies which all point to some powerful neurogenesis effects of mindful medication and resulting reduction in anxiety.

One example out of many:

Seventy-eight percent of treated participants no longer met criteria for GAD and 77% achieved high end-state functioning at post-treatment assessment; these proportions stayed constant or increased over time.

That is, the aerobic exercise group demonstrated an increase in volume of the left and right hippocampus by 2.12% and 1.97%, respectively, over the 1-y period, whereas the stretching control group displayed a 1.40% and 1.43% decline over this same interval

Stress toxicity could also favor hyperactivity in the amygdala which may enhance fear responses to environmental cues while decreasing neural inhibition in dlPFC and ventromedial PFC; chronically stressful conditions can fail to maintain effective executive control over limbic overdrive.

The curious effect of CFR and SSRI's for anxiety and depression

They basically boost levels of serotonin available to neurons in the brain.

The problem is that serotonin is a workhorse of signaling in the brain.

Boost it in one area and you might get a reduction in anxiety.

Boost it in another, any might get an increase in anxiety.

This is exactly what happens with SSRI's and CFR.

There's a curious result of a person just starting SSRI's for anxiety.

For the few two weeks, there can be an INCREASE in anxiety or depression.

If SSRI's, and more importantly, serotonin, is so ideally suited for the condition, why would we see an initial increase in the very thing we're trying to address?

CFR.

It's a cascade effect the net result is more CFR which causes more anxiety:

Kash and his team observed that the anxiety-mediating BNST neurons expressed the stress-signaling molecule corticotropin releasing factor (CRF). When they added a compound to block CRF activity, they witnessed that fearful behaviors -- which had been triggered by fluoxetine -- were greatly reduced.

Interestingly, when the CFR is blocked separately, the anxiety effects of the SSRI are reduced:When the team added a compound to block CRF activity, the fear and anxiety that had been triggered by the Prozac were greatly reduced.

This is why many doctors will prescribe benzodiazepines (like Xanax,Ativan, or Valium) for the first few weeks.

They'll often say this is because it takes time for SSRI's to kick in but that's not entirely true.

It's to mask the increased anxiety or depression:

Combine this with the fact that SSRI's normalize (effect goes away with time), have significant side effects, and are generally helpful in 30% of those prescribed.

That's for depression.

In general, the SSRI's work better for people who have anxiety along with depression.

Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB1R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress

The full puzzle can be found at our histamine, CBD, and anxiety article above.

We crafted IndigoNaturals based on research and the research is all for CBD by itself.

CBD Isolate.

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https://indigonaturals.net/blogs/news/can-cbd-cause-anxiety-rebounds2019-05-13T22:17:15-07:002019-05-13T22:17:15-07:00Can CBD Cause or Be Used For Anxiety ReboundsIndigo Naturals
Can CBD Cause or Be Used For Anxiety Rebounds

Learn how CBD works on the anxiety circuit in terms for rebound anxiety

CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement

What about normalization...the ability to build up a tolerance where the chemical has less and less effect?

They also conclude from their survey, that none of the studies reported tolerance to CBD.

As for addiction, the news is even better.

Where benzos create a rush of dopamine (key circuit for addition), CBD is actually showing much promise to offset addiction.

This is especially true for THC addiction (yes, it's addictive for a percentage of the population) and opiates.

Check out this study and the resulting effect of CBD on rebound anxiety from cannabis withdrawal:

CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.

Best type of CBD for anxiety

Full spectrum will have lots of plant material and potentially up to .3% THC.

This is not great news for people with histamine issues.

That's roughly 40-60% of the population.

Women are higher on that scale are as people over age 40.

That's why we focus on CBD Isolate.

More importantly, all the research (dozens of studies) are for CBD by itself.

Not full spectrum. Not CBC. Not CGN. Not hemp oil.

CBD by itself.

We crafted IndigoNaturals based on what research was showing for anxiety.

Our story is here but we found out the hard way after 3-4 bottles of full spectrum CBD caused lots of histamine issues.

THC can actually cause anxiety in the research so there's no reason to have that there as well.

Let know us know how CBD works for you for anxiety rebounds.

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https://indigonaturals.net/blogs/news/what-research-shows-for-cbds-effects-on-stress-and-anxiety2019-05-10T22:51:00-07:002019-05-10T22:53:22-07:00What Research Shows for CBD's effects on Stress and AnxietyIndigo Naturals
What Research Shows for CBD's effects on Stress and Anxiety

Learn how CBD affects the key system tied to stress response as it pertains to anxiety

A research team led by Carnegie Mellon University's Sheldon Cohen has found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response

"Inflammation is partly regulated by the hormone cortisol and when cortisol is not allowed to serve this function, inflammation can get out of control,"

Essentially, the immune system becomes less responsive to Cortisol's balancing act if it's always present.

Very similar to our body's response to constant sugar...diabetes!

They went on to say...

When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease.

Other studies have showed this same effect with cortisol having so called "biphasic" effects on inflammation.

Excessive cortisol (from chronic stress) poses its own issues in terms of anxiety:

Exaggerated or recurrent negative cognitions, rumination or worry, magnification, and helplessness are all maladaptive catastrophizing responses to pain or non–pain-related stress that may prolong cortisol secretion

Scientists have learned that animals that experience prolonged stress have less activity in the parts of their brain that handle higher-order tasks — for example, the prefrontal cortex — and more activity in the primitive parts of their brain that are focused on survival, such as the amygdala.

In fact, recent research showed that THC thickens the amygdala in such a manner.

The biggest differences in gray matter were in the amygdala, which is involved in fear and other emotion-related processes, and in the hippocampus, involved in memory development and spatial abilities.

Remember that powerful thoroughfare of communication between our scaredy cat (amygdala) and voice of reason, the prefrontal cortex.

The uncinate fasciculus (say that 5 times fast).

Chronic stress early in life can affect this communication link as well:

Exposure to intense and chronic stressors during the developmental years has long-lasting neurobiological effects and puts one at increased risk for anxiety and mood disorders

When that bike is about to crash into you, calm is not the response that will keep you (or your ancestors) alive.

Adrenaline and Cortisol is more needed!

Long term, chronic stress however will depress GABA levels which is directly tied to anxiety.

Chronic stress causes disinhibition of the hypothalamus-pituitary-adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress-related disorders, e.g. depression.

What about serotonin (more tied to depression but also present with anxiety circuit).

An interesting study showed that in health subjects, cortisol (our main stressor chemical) would boost serotonin but not in subjects with depression or anxiety:

A significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the control group, whereas neither the generalized anxiety disorder nor the major depression group exhibited changes in serotonin uptake upon incubation with cortisol.

The various chemicals interact at specific receptors throughout the brain and body known as CB1 and CB2 receptors.

The research went on to say:

Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors.

Let's put the pieces all together now:

With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior

Put a note next to Anandamide for when we discuss CBD below (very exciting).

Back to the question we had at the beginning...why do some people have one stress response while another person has a completely different stress response?

translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder.

However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically.[3] This may result in significant damage to cell structures.

Collateral damage to surrounding tissue and since it's in the brain, that's valuable real estate.

To be more specific:

They also trigger numerous molecular cascades, leading to increased blood-brain barrier permeability (through activation of matrix metalloproteinases and subsequently degradation of tight junctions), alterations of brain morphology, neuroinflammation, and neuronal death

The research is all based on CBD Isolate!

To be safe, shouldn't the product we put in our bodies mirror this same research!

Yes!!

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https://indigonaturals.net/blogs/news/can-cbd-help-with-general-anxiety-disorder2019-05-08T19:57:32-07:002019-05-08T19:57:32-07:00Can CBD Help with General Anxiety DisorderIndigo Naturals
Can CBD Help with General Anxiety Disorder

Learn what research is showing for CBD's effects on the "trait" anxiety pathways

This could mean that people with the disorder have a harder time discerning truly worrisome situations from mild annoyances.

This study and others also found too much connection with the prefrontal cortex and too much activity there:

At the same time, the amygdala was more connected to a cortical executive-control network previously found to exert cognitive control over emotion.

Something in this circuit between the two areas is off-balance.

Another study found:

The results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying

This misrouting may be due to weak connection at one key choke point in this whole fear-rational circuit:

In this case, two types of scans showed the amygdala, which alerts us to threat in our surroundings and initiates the “fight-or-flight” response, seems to have weaker “white matter” connections to the prefrontal and anterior cingulate cortex (ACC), the center of emotional regulation.

the imaging showed the brains of people with GAD had reduced connections between the prefrontal and anterior cingulate cortex and the amygdala via the uncinate fasciculus, a primary “white matter” tract that connects these brain regions.

More importantly…

This reduced connectivity was not found in other white matter tracts elsewhere in their brains.

We discussed the anterior cingulate cortex in our CBD for anxiety article.

The uncinate fasciculus is a new actor though.

The plot thickens.

Research is showing this communication tract between our Amygdala and the prefrontal cortex is critical to anxiety:

The UF-amygdala complex may be pivotal for the control of trait anxiety.

increased frequency of anxiety disorders after TBI may reflect an overlap between brain regions vulnerable to traumatic brain injury, and the neural circuitry of these disorders.

We've talked about some of the circuits at work (amygdala/prefrontal cortex, the uncinate fasciculus, etc).

What about infection and inflammation?

This is where there's really exciting new research.

The tell-tale signs of both (immune response) is all over general anxiety disorder:

analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression.

GAD is general anxiety disorder of course. Those strange chemicals are all inflammatory immune responders.

Did you notice that last little piece…"independent of the presence or degree of depression".

That's really important.

They found these various immune agents elevated for anxiety by itself!

There are dozens are studies like this all pointing in the same direction.

Immune response (which governs how our body deals with both infection and inflammation) is higher in people with general anxiety disorder!

Put a checkmark next to that for when we get to CBD. Very exciting.

One last stop...the gut!

Gut Dysbiosis

This is the new Wild West of health...the trillions of bacteria in our gut.

How does this affect general anxiety disorder?

When they compared healthy people's guts versus those with general anxiety disorder, there were marked differences:

Compared with the HCs, we found markedly decreased microbial richness and diversity, distinct metagenomic composition with reduced short-chain fatty acid (SCFA)-producing bacteria (associated with a healthy status) and overgrowth of bacteria, such as Escherichia-Shigella, Fusobacterium and Ruminococcus gnavus

It was the only area showing reduced activity in the brain scans of people with GAD.

People who use cannabis showed reductions in volume for that very important communication link:

Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus.

It shows that the underlying endocannabinoid system is governed with "balancing" brain signaling for CBD to have this effect.

Remember that the net result of brain injury, inflammation or genetic variations with general anxiety disorder is irregular signalling (not enough GABA, not enough serotonin in specific areas, etc).

The ability of CBD to boost this balancing mechanism is fascinating.

What about actual brain structure? That's a long term consideration with GAD.

Remember how we noted that THC has been shown to adversely affect brain areas?

Most of the research on CBD on brain structure results from its protective role against these changes from THC.

THC's effects are here:

Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum).

Don't assume tomorrow is like today. The CRSPR technology looks to totally revolutionize medicine and it's coming sooner than the naysayers tell.

Genetics are at the root of this issue and we'll use CBD to get us there!

Be well and be hopeful even when it's the hardest thing to do.

We've been there!

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https://indigonaturals.net/blogs/news/can-cbd-help-with-panic-attacks2019-05-04T16:41:00-07:002019-05-22T11:00:46-07:00Can CBD Help With Panic AttacksIndigo Naturals
Can CBD Help With Panic Attacks

Fight or flight. Freezing. All this behavior resides here. It's the brain processing center for dread!

Researchers found hyperactivity in scans during panic attacks at the DPAG area:

Stimulation of the dorsal and lateral aspects of the PAG can provoke defensive responses characterised by freezing immobility, running, jumping, tachycardia, and increases in blood pressure and muscle tonus.

Chronic restraint stress produced approximately 3% reduction in hippocampal volume

This is directly tied to anxiety, depression, and a host of mental health issues.

Anxiety figures into this…

Pathological anxiety and chronic stress are associated with structural degeneration and impaired functioning of the hippocampus and the prefrontal cortex (PFC), which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia

Orexin, produced in a circuit emanating from the brain's hypothalamus, regulates arousal, wakefulness and reward

There's an ingenious experiment in which the researchers used a special salt (sodium lactate) which causes panic responses.

It directly boosts levels of orexin in the brain.

When they blocked the genes for orexin production, the panic response went away.

When they looked at people...it got more interesting:

Those with panic disorder had higher levels of orexin than those without panic disorder. In addition, those with only panic anxiety had significantly higher orexin levels than those with major depression accompanying their panic anxiety.

Interestingly, Zoloft, an SSRI was shown to reduce orexin levels.Granted with some nasty side effects.

The results showed that repeated but not acute peripheral administration of CBD decreases escape responses in the ETM, suggesting a panicolytic effect.

This speaks to CBD literally supporting new brain connections and areas.

Speaking of long-term effects on panic disorder, remember the whole hippocampus area discussed above and neurogenesis (making new brain mass and connections)?

This may be our favorite aspect of CBD across a host of mental health issues and aging in general:

In addition to serotonin, other mechanisms might be involved in the anti-panic effects of CBD. For instance, chronic treatment with CBD can increase the anandamide levels within the hippocampus with concomitant increases of hippocampal neurogenesis

In fact, a powerful antihistamine is also known to have a powerful anti-anxiety effect!

We focus on CBD Isolate for a reason.

All the plant material in "full spectrum" that everyone is selling (based on scant research) is likely to cause a nasty histamine response.

40-60% of people have histamine issues.

That number goes higher for women and higher yet for women over 40!

We found that out the hard way by trying 3-4 big brands of full spectrum CBD (because we we're told they were so much better) with nasty side effects.

That's how we eventually found CBD Isolate and based on our experience and research (see above...we don't mess around), crafted IndigoNaturals.

We really want people to feel better and at the lowest cost per mg of CBD available with:

Organically grown in the US

3rd party tested

THC free (huge histamine issue plus other problems)

CO2 processed

Bacteria free

Mold free

Solvent free

Heavy metal free

Pesticide free

Our whole family uses IndigoNaturals (anxiety was one issue...see our story here).

Perimenopause hormone drop sent me to the ER 3 times with panic attacks.

I know all too well how this feels and what CBD can do for it!

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https://indigonaturals.net/blogs/news/can-cbd-help-with-public-speaking2019-04-29T23:03:00-07:002019-05-21T17:02:18-07:00Can CBD Help With Public Speaking Anxiety?Indigo Naturals
Can CBD Help With Public Speaking Anxiety?

Check out the research study on how CBD helps with public speaking anxiety

That effect may be magnified by the so-called "illusion of transparency" which states that people tend to overestimated other people's ability to understand their mental state.

That speaks to feeling emotionally naked or laid bare when in front of people publicly.

Once the circuit is triggered, you feel that the audience can know how you feel internally which just furthers that circuit along.

The second theory is one of happenstance.

Why public speaking?

Yes, this a is form of performance anxiety but it's very distinct.

We are not going to get physically hurt from public speaking. There's no risk to life...physically anyway.

There's unique area of the brain called Pregenual Anterior Cortex

That's a mouthful but stick with us...it's very interesting for social anxiety issues such as public speaking.

Think of the anterior cortex as a translator between our old primitive brains (amygdala, hippocampus, etc) and the shiny, modern, thinking brain (prefrontal cortex).

A lot of the peculiar thinking abilities that make us human are the result of these "middlemen" or circuits.

The pregenual anterior cortex is really interesting.

Among other things, it's the seat of:

Social evaluation

Social rejection

Combine this with an active amygdala and you have fear of being rejected, judged, and more.

It's really the seat of self-conscious feelings!

Ding ding ding. Fear of public speaking and performance in general.

Yes, there may be an evolutionary aspect (fear of rejection from small tribe was genuinely dangerous) but the nonsensical reaction to public speaking that 3/4rds of us have may just be a glitch in the system.

Again, it wasn't going to kill our ancestors...just embarrass them.

So...what does CBD have to do with any of this?

The study on CBD and public speaking anxiety

Let's walk through the specific study on CBD and public speaking.

There were three main groups of people in a double-blind experiment:

Placebo given 1 hour prior to public speaking test600 mg of CBD given 1 hour prior to publich speaking testGroup given nothing prior to public speaking test

The people were also separated further into people without anxiety issues and those with known anxiety issues.

Results were given in three different categories:

Visual Analogue Mood Scale (VAMS) - how the person appears to the researchers

Negative Self Statement Scale (SSPS-N) - the test subject's view of their state

Physiological criteria - blood pressure, heart rate, skin conductance

The results were impressive.

Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech.

For this reason,we want clean CBD isolate to avoid the very excitatory histamine release.

Stress itself can increase histamine release and public speaking is definitely in the "stressful" category.

We specifically crafted IndigoNaturals for anxiety and histamine response.

Keep in mind that the same calculus applies to performance anxiety in general.

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https://indigonaturals.net/blogs/news/is-tryptophan-the-connection-between-inflammation-and-anxiety2019-04-27T22:22:33-07:002019-04-27T22:22:33-07:00Is Tryptophan the Connection between Inflammation and Anxiety?Indigo Naturals
Is Tryptophan the Connection between Inflammation and Anxiety?

Learn how tryptophan is a critical player between inflammation and anxiety plus what CBD can do to support it.

Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice

In another study on people, researchers submitted test subjects to oxygen deprivation.

Some of them had a placebo while others received a supplement dose of tryptophan.

The ones without tryptophan had a much stronger anxiety and panic response to the stressful event.

Furthermore, a significant increase in neurovegetative panic symptoms occurred after the CO2 challenge.

They went on to say…

We conclude that the serotonergic system is causally involved in anxiety-related mechanisms and that it may be worth pursuing the role of tryptophan depletion on CO2-induced panic in patients with anxiety disorders.

cannabidiol modulate mitogen-induced tryptophan degradation

The net result…

suppression of tryptophan degradation by cannabinoids via indoleamine-2,3-dioxygenase, which is independent of cannabinoid receptor activation, might enhance the availability of tryptophan for serotonin biosynthesis and consequently can be important in the action of cannabinoids to improve mood disturbances.

The eCB-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system.

Endocannabinoids were even found as crucial in the area of the brain that releases serotonin in response to stress:

The glucocorticoid-induced inhibition of glutamatergic transmission was mediated by the activation of postsynaptic G-protein-coupled receptors and signalled by retrograde endocannabinoid (eCB) messengers

This sounds pretty confusing but to translate.

Stress chemicals tell the serotonin production area of the brain to ramp up VIA the endocannabinoid system!

Thus, the compensation of tryptophan degradation might be an important mechanism, by which THC and CBD may improve mood disturbances and quality of life, especially in diseases associated with inflammation.

first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction.

As a whole, the nucleus accumbens has a significant role in the cognitive processing of motivation, aversion, reward (i.e., incentive salience, pleasure, and positive reinforcement), and reinforcement learning

Benzodiazepines’ newly discovered mechanism for producing reward is comparable to those of opiates, cannabinoids, and GHB.

The road to addiction deals with structural changes in the brain as the continued use of benzos start to change the structure of the brain to respond more strongly to future

These receptors render the cell more susceptible to stimulation by the excitatory neurotransmitter glutamate, and as a result, the cells respond to future drug exposures with larger dopamine surges that produce even more intense pleasure.

Furthermore...their assessment after watching structural changes in the dopamine neurons:

Even if you clear the drug from the body, there are long-lasting changes in brain architecture.”

Xanax causes addiction in much the same way that other drugs, including opiates like oxycodone, cause addiction

It's half-life is roughly 6-29 hours. Peak levels are usually in 1-2 hours and it's cleared primarily by the kidney.

Xanax has one of the shortest durations of any of the benzos and has no metabolites so lessen the drop off.

This might be why it has a street value and a slew of nicknames on the streets.

There's even a rapper called Lil Xan and it punctuates a great deal of the soundcloud rap scene despite being involved in the death of many prominent entertainers.

Last we check, there was no rapper called Lil Oxy.

CBD's peak level is from 4-6 hours and generally lasts about 24 hours in the body.

More importantly, CBD doesn't cause the rush of dopamine associated with Xanax.

Studies have shown that it not habit forming or hedonic.

Hedonic is the key there.

It's a scientific word that means pleasure causing. Remember the dopamine rush centers were tied to pleasure and behavior reinforcement for Xanax and other benzos.

CBD studies have shown it to be:

Non-hedonic

Non habit forming

Not subject to normalization (need more and more for same effect)

Not psychoactive

These are the key differences between CBD and Xanax.

In 2013…

national ED visit data and national prescription data show that alprazolam is related to more ED visits related to drug misuse per prescription (1 in 311) than the next 3 most commonly prescribed benzodiazepines—lorazepam (1 in 540), diazepam (1 in 517), and clonazepam (1 in 321)

Okay, #1 is zoloft which had the worse adverse reactions and low relative effectiveness.

#2 is Xanax, a very short acting and addictive benzo (more here on CBD versus benzos)

#3 is Lexapro which had the least improvement over placebo.

Then there's #11 (which is why we didn't stop at 10!) which is Effexor.

Notice how they're all listed for depression except for the benzo??

More importantly, where's Prozac?

It was ranked highest in both response (improvement) and remission (drop in HAMA score below 7) with adverse reactions way below Zoloft.

Hmmm...if we were cynical...we won't go there.

But the numbers do!

These results are good but not nearly as strong as for benzos since they directly affect GABA levels (much more relevant for anxiety).

The downside of benzos are plenty can be found at our CBD versus benzos for anxiety.

SSRI's were the least of two evils in terms of treating anxiety essentially.

Don't get us started on the simple antihistamine hydroxyzine:

Efficacy was maintained throughout the 4 weeks of treatment and after abrupt discontinuation. In another controlled trial vs. lorazepam, hydroxyzine demonstrated greater and more rapid cognitive improvement.

The effects on Glutamate and GABA are varied depending on where you are in the brain.

Like we said, serotonin is a workhorse of brain signaling!

Here's the deal.

No doctor can test if you're "low" in serotonin.

They just go based on symptoms (depression).

For anxiety, it's not even a good proxy but they're trying to avoid the serious side effects of benzos.

Too much serotonin has actually been tied to social anxiety.

Increasing serotonin can cause anxiety during the first few weeks (by boosting CFR.

An excess of serotonin can cause a host of nasty side effects and worse (serotonin syndrome).

So the question begs…

Can we get neuroplasticity, serotonin balancing, and anti stress and inflammation a different way?

We're almost there.

One more stop.

The endocannabinoid system and serotonin

Before jumping into CBD, let's look at the system it operates in….the endocannabinoid system.

Every living animal has one and recent research are showing it's critical to balancing other key systems:

Nervous system - including neurotransmitters like serotonin, GABA, and Glutamate

Endocrine system - hormones including histamine and others

Immune system - inflammatory responders like cytokines and microglia (in the brain)

Since SSRI's are primarily concerned with boosting serotonin, our question is how serotonin and the endocannabinoid system interact.

Do they at all?

Yes!

Remember that the basic role of the endocannabinoid system that researchers have teased out is that a regulator.

Finding balance in other systems.

Serotonin is a neurotransmitter and under the same governance as any other player in that system.

To put a point to it…

Ample evidence from behavioral studies also suggests that eCBs are important regulators of stress responses and a deficit in eCB signaling contributes to stress-related disorders such as anxiety and depression.

"eCB's" is short for endocannabinoids which we have naturally in our brain and body.

How does it exert its effect on stress response?

The eCB-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system

Let's get right to the point...what's the effect of SSRI's on Anandamide.

We thought you would never ask!

Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase.

The amygdala is the seat of our fear and emotional response and intimately tied to anxiety.

Wow.

Fluoxetine is Prozac...the first of all SSRI's.

To make it easier for the rest of us to understand..

There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs.

The mechanism for this brain alteration is via the endocannabinoid system.

One final piece from this fascinating study:

electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA.

Let's translate please.

The SSRI fluoxetine increases anandamide (an endocannabinoid) which causes a calming effect of the Amygdala where anxiety is driven.

We could literally stop right there.

But we won't!

What does any of this have to do with CBD?

CBD versus SSRi's for anxiety according to research

First, does CBD even operate on the same pathways as SSRI?:

Neurogenesis in the hippocampus

Serotonin pathways

GABA and Glutamate levels

Yes. Yes. and resoundingly Yes.

Let's look at research (always).

We mentioned neurogenesis or the remodeling of brain pathways and circuits being a primary effect of SSRI's (which is why they take so long).

Remember that benzos can affect anxiety almost immediately (which is part of the the problem...see CBD versus Benzos for anxiety).

SSRI can actually INCREASE anxiety and depression in the first 2 weeks.

We explain why this happens in our CBD for anxiety article but it speaks to Serotonin being such a multifaceted taskmaster of neurotransmission.

Masking increased anxiety/depression for first few weeks of use with benzos

Significant list of side effects

Serotonin Syndrome for people who already have higher levels of serotonin

Serotonin Discontinuation Syndrome - can we call it what it is??

Let's look at these and then compare with safety research on CBD.

Research shows no initial increase of anxiety/depression when initially taken.

Remember, it does not "juice up" the levels of serotonin like SSRI's.

If too low, it boosts serotonin levels. If too high, it actually works with endocannabinoid system to rein in the level.

That's the role of the endocannabinoid system.

How many times have seen "modulate", "balance", "homeostatis" in the research?

There has not been a known overdose of CBD. Research has tested it up to 1500 mg with a strong safety profile.

For anxiety, the top range is probably up to 300 mg according to research (we'll explain why below).

What about side effects?

CBD's common side effects are:

Drowsiness

Lowered blood pressure

Lightheadeness

Dry mouth

What about SSRI's side effects?

Thirty-eight percent of the approximately 700 patients surveyed reported having experienced a side effect as a result of taking a selective serotonin reuptake inhibitor antidepressant; the most common side effects mentioned were sexual functioning, sleepiness, and weight gain.

On the general effects of SSRI's on serotonin and the gut biome, there's a great review here:

How much CBD to match effects of SSRI

One study directly looked at this question.

They studied 3mg per kg of body weight and 30 mg per kg of body weight.

The 3mg per kg of body weight had the best effect on anxiety and neurogenesis:

Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus.

The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state.

CBD is a powerful anti-inflammatory and most importantly, is a powerful ally against neuroinflammation:

cannabidiol (CBD) has emerged as a promising strategy to treat inflammation that results from microglial hyperactivation [78], with no psychotropic side effects. Moreover, CBD has been shown to attenuate oxidative and nitrosative stress in several human disease models

We went through about a dozen NIH studies on anti-anxiety medications...anxiolytics as they're called.

Call them what you will as long as they work and we're not taking on a major addiction!

Towards the end of a pretty comprehensive overview of anti-anxiety meds, there was a 1-2 sentence blurb that caught our attention towards the very bottom of the list of meds.

The article first went through:

Benzodiazepines (the next opioid addiction)

SSRI's (serotonin boosters with a host of issues)

Triciclates (old serotonin boosters out of favor due to negatives)

BuSpar

And then there it was….hydroxyzine.

Hmmm.

It's a very old medication with very little side effects.

Since this is personal for us (2017 was a year of intense, rolling anxiety due to perimenopause), we like to turn over every stone.

The more we researched hydroxyzine for anxiety, the more curious we were.

It primarily acted on the histamine receptors, H1 as they're called.

Yet, its effectiveness rivaled benzo's for anxiety!

We knew that there was a tie between histamine release and anxiety...especially for the 40-60% of the population that has histamine issues but this was shocking.

What gives??

Why are we prescribing billions of dollars in SSRI's and benzos with incredibly significant knock on effects (see the article on anxiety meds versus CBD for the full scoop), when a simple and effective histamine med has been around for decades?

Our jaded side can answer that question but more importantly, just how deep is the underlying connection between histamine and anxiety?

Now, that's a question we want to get to the bottom of.

Let's go there now!

We'll cover these topics:

A quick look at histamine's function

Histamine and GABA

Histamine and Glutamate

How histamine affects anxiety

How CBD affects histamine

The best CBD for histamine and anxiety

What dose for histamine and anxiety

Let's get started.

First...what is histamine (besides the thing that is "anti" in antihistamine!)?

A quick look at histamine's function

Most of us know histamine for its over-active reaction to pollen, pet dander, and an assorted list of allergens.

Yes, it's in charge of the allergic response we have to many substances (increasingly by the way) but it does so much more.

Histamine is also a powerful neurotransmitter in the brain!

Let's quickly look at both aspects since it will all figure into our discussion of anxiety and CBD.

First, Histamine as an Allergic and Inflammatory agent

This is how most of know histamine (unfortunately)

It's part of our immune response and its role is straight forward.

Upon detection of foreign entities, get them out quickly!

The result is redness, swelling, itching, sneezing, coughing, and general constriction everywhere.

Again, get an allergen out fast.

Histamine is generally released from Mast Cells located throughout the body.

The name comes from a german word meaning "fattening" since they're jam-packed with histamine ready to be released.

CB2 has been shown to play a role in allergic inflammatory responses, being expressed by many immunologic cells including eosinophils, neutrophils and mast cells.

CB2 stands for cannabinoid receptors found throughout the immune system.

To put a point to it…

As a modulator of many immune and inflammatory responses, the ESS could potentially be harnessed for use in the management of a variety of disease processes including wound healing, acute and chronic inflammatory disorders, and cancer.

Let's look at CBD specifically.

A quick recap since we now see the connection between histamine release and anxiety.

First, most of the research is on CBD and "allergies" which is fine since that's just the end result of histamine release.

Let's start with allergic airway diseases (asthma, etc).

In one study:

CBD treatment decreased the inflammatory and remodelling processes in the model of allergic asthma.

The mediator of this cross-talk between the body and the brain's response appears to be microglia...our brain's local immune responder.

As the cop on the beat (the brain), it gets a call from headquarters (immune system) to be on the lookout.

The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention.

This just means that if the microglia respond incorrectly, damage can occur in the brain.

These changes in inflammation were not associated with injury severity; suggesting that the association between inflammation and the expression of behaviors characteristic of decreased psychological well-being was not confounded by differential impairments in motor ability.

Another large study sought to measure the actual component pieces of inflammation in people with anxiety.

The found that inflammation markers were elevated in people with anxiety in two situations:

If you're part of the 51% of the population where progesterone and the three different versions of estrogen are important, this is a must read article.

That "late-onset" aspect is also interesting.

This hints at infection and/or inflammatory roots for the anxiety.

The researchers are getting more sophisticated where they can look at specific parts of the brain now.

Now with imaging technology, we can see what's actually happening in the brain in terms of inflammation in people with anxiety:

Inflammation was consistently found to affect basal ganglia and cortical reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including amygdala, insula and anterior cingulate cortex, which may result from cytokine effects on monoamines and glutamate.

increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines.

There can even be a feedback loop between our body's stress response and our anxiety response:

Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus).

There's the Amygdala again. Notice how "cytokines" popped up in the prior paragraph?

Let's go there now.

Cytokines are the heavy lifters of the immune system's inflammatory response.

That's a mouthful!

Seriously though.

This is a general catchall for any immune agent that can affect other cells.

It can include:

Interferon

interleukin

growth factors

And more!

It's a zoo of different chemicals our body uses to protect and repair us with.

Do cytokines do other things besides attack bad things in the brain?

cytokine signaling in the brain is known to regulate important brain functions including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, as well as the neural circuitry of mood.

activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements

Okay...now we're talking.

Glutamate is our brain's excitory chemical and it looms large in our research on anxiety. Too much gas pedal!! (See here)

Oxidative stress is highly destructive to neurons (long term) and it's been tied to anxiety

Glial elements - those are the microglia immune responders in the brain that go haywire!

You'll see that these same components (in different measure) are implicated in both anxiety and depression.

The two have a close association (such as side effects for the main anxiety medications!).

Of those with a depressive disorder, 67% had a current and 75% had a lifetime comorbid anxiety disorder. Of persons with a current anxiety disorder, 63% had a current and 81% had a lifetime depressive disorder

Elevated IL-8 production capacity in both previously and currently depressed and anxious persons might indicate a genetic vulnerability for these disorders.

Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-a /IL10, TNF-a /IL4, IFN-? /IL10, and IFN-? /IL4 in the GAD group compared to the control group.

Again, GAD is General Anxiety Disorder.

Okay...we could go and on from research.

It's clearly showing a link between inflammation and anxiety.

Let's look at the endocannabinoid system before we jump to CBD.

How does the endocannabinoid system moderate inflammation and anxiety in the brain

The endocannabinoid system spans our entire body and there are receptors on almost every type of cell (except red blood cells).

It's tasked with balancing three key systems:

Nervous system - neurotransmitters tied to anxiety like GABA, Glutamate, and Serotonin

CB1 is a cannabinoid receptor in this system generally found in the brain.

IL-1 is short for interleukin 1, a cytokine or immune system responder

More importantly, the endocannabinoid system (eCB) may be the intersection between stress response and inflammation.

eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders.

microglial cells could be a target for cannabinoid influence on psychiatric disorders, such as anxiety, depression, schizophrenia, and stress-related disorders.

In fact...the endocannabinoid system may govern how microglia cells respond:

Evidence now shows that microglia, the macrophages of the brain, also express a functional eCBSS and that activation of CB receptors expressed by activated microglia controls their immune-related functions.

Microglia are polarized to M1 type in high-anxiety inbred mice in response to lipopolysaccharide challenge

Stressful experiences such as social defeat activate long-lasting peripheral and central immune response (10–12) and induce microglial activation, myelopoiesis in the bone marrow and spleen, infiltration of monocytes into the brain and neuroinflammation

That might be critical to PTSD, teenage anxiety, and social anxiety.

Again, it's one of many examples.

Let's end with a very specific study on anxiety, the endocannabinoid system, and IL1, a cytokine.

Here's the smoking gun connecting all three:

We found that a single intracerebroventricular injection of IL-1 caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum.

We're going to focus on brain inflammation and CBD below since anxiety has been tied most closely to this.

We've evaluated different aspects of inflammation and anxiety including:

Cytokines (inflammatory actors)

Microglial cells (the immune actors in the brain)

Let's start generally and work down to these pieces.

First, CBD appears to also aid the serotonin pathway to protect the brain:

CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans.

These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.

It's short for oligodendrocyte which is a type of microglia cell in the brain and nervous system.

Basically, CBD was able to protect these cells during stress response to calm our immune action in the brain.

Remember that overactive microglial cells are tied directly to anxiety:

Hyperactive microglia, a common feature of these neurodegenerative diseases, secrete a number of pro- and anti-inflammatory cytokines, chemokines, glutamate, prostanoids, neurotrophic factors, and a range of free radicals that provide a milieu for oxidative stress.

How does CBD affect this pathway?

CBD has been shown to attenuate oxidative and nitrosative stress in several human disease models

Since puberty is a giant flux in hormones (which we'll touch on below), how do they figure into this process?

Indeed, the amygdala is one of the few regions of the brain that contains both estrogen and androgen receptors [16-18], indicating that its function may be directly influenced by hormonal changes during puberty.

The endocannabinoid system has been shown to have a powerful effect on:

Serotonin signaling

GABA signalling and balance with Glutamate

Histamine response

Hippocampus neurogenesis

Reducing neuroinflammation

Balancing brain activity (see research on CBD and psychosis)

That all stands true for teenagers but let's look at the ECS (endocannabinoid system) and puberty.

Is it involved in that process within the brain?

Yes!

Emerging evidence suggests that during adolescence, changes in eCB signaling contribute to the maturation of local and corticolimbic circuit populations of neurons, such as mediating the balance between excitatory and inhibitory neurotransmission within the prefrontal cortex.

Again, other medical interventions did not work and her symptoms deteriorated.

CBD (cannabidiol) was a last-ditch effort for both her anxiety and insomnia.

A gradual increase in sleep quality and quantity and a decrease in her anxiety were noted. After 5 months, the patient was sleeping in her own room most nights and handling the new school year with no difficulties. No side effects were observed from taking the CBD oil.

Patients with LGS taking cannabidiol oral solution at 20 mg/kg/day in two clinical trials saw a 42%-44% reduction in drop seizure frequency over a 14-week treatment period

This study gives a good track record for CBD's long term effect during puberty since we now have more data and these kids have gone through puberty using CBD for epilepsy.

We do not see developmental issues as a result in that reserach

Just a side note...research is showing that some stress during puberty actually primes the brain for being better able to handle issues later in life:

In fact, a certain amount of stress exposure or socio-environmental stimulation is probably necessary for normal development and exerts long-term stress-protective, anxiolytic, and antidepressant effects later in life [240, 277, 355, 356]

Remember how we discussed the "fear" and "threat response" circuits of the brain during puberty and teenage years.

It's a tug of war that's temporarily being won by the Amygdala while the prefrontal cortex is closed for remodeling.

What does CBD do here?

CBD is associated with increased resting cerebral regional blood flow (rCBF) in the left parahippocampal gyrus and decreased rCBF in the amygdala-hippocampus complex, including the posterior cingulate cortex

To translate...imaging showed that activity slowed down in the area that's in overdrive for fear and emotional response during teenage years.

This showed especially during a time of highly charged emotional response:

A functional neuroimaging (fMRI) study found evidence for attenuation of the blood-oxygen level dependent (BOLD) signal in the amygdala and the posterior and ACC in response to the presentation of fearful faces, combined with a reduction in subjective anxiety

We talked about fearful faces and the awakening of the teenage brain to social scrutiny above.

Their synopsis:

Taken together, these results point to both an anxiolytic effect of CBD and a critical modulatory role of the ACC.

The Anxiety meds article goes through safety for the common anxiety meds and our experience with those is what drove us to study and try CBD.

Do the research. Be your own advocate. Make an informed decision.

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https://indigonaturals.net/blogs/news/the-amazing-connections-between-cbd-and-the-woman-who-never-felt-pain-or-anxiety2019-03-30T20:53:00-07:002019-04-01T15:37:58-07:00The Amazing Connection between CBD and the Woman Who Never Felt Pain or AnxietyIndigo Naturals
The Amazing Connection between CBD and the Woman Who Never Felt Pain or Anxiety

The intersection of CBD's effect in the body and a woman who can't feel pain or anxiety is amazing

These results suggest that anandamide-mediated signaling at peripheral CB₁ receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.

It's actually pretty frustrating to us after seeing all the buzz about this woman who can't feel pain or anxiety.

This relationship is all over NIH research as you see in that specific article.

Many brands will say…"Hey, it's a small amount!".

Not for people with anxiety!

Look, roughly 24-36% of the population is allergic to THC.

Small amounts have very negative effects (the bad trip from cannabis is likely due to this) including pretty intense anxiety and paranoia.

The small amounts in legal full spectrum CBD is enough to make you fail a drug test so clearly, it's adding up in the system.

CBD has shown powerful effects with anxiety. That's all the research is showing.

For that reason, CBD Isolate is a better option than full spectrum for anxiety.

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https://indigonaturals.net/blogs/news/can-cbd-help-with-social-anxiety2019-03-29T20:54:00-07:002019-05-21T16:32:44-07:00Can CBD Help With Social Anxiety?Indigo Naturals
Can CBD Help With Social Anxiety?

Learn what research is showing for CBD and social anxiety specifically

Let's look at social anxiety including the specific topics covered above:

Amydala - Prefrontal cortex signalling

Serotonin signalling

Pregenual Anterior Cingulate Cortex

Fear Extinction

Let's first introduce two key endocannabinoid players in our brains:

2-AG

Anandamide

These are cannabinoids that are found naturally in our brains.

They are directly involved with social anxiety:

studies targeting cannabinoid receptors and transmitters [anandamide and 2-arachidonoyl- sn-glycerol (2-AG)] have found regulatory effects, particularly in social anxiety and social reward, as well as endocannabinoid dysregulation in social impairment related to neuropsychiatric conditions.

What was fascinating is that this early exposure showed its effects (similar to social anxiety in people) via the endocannabinoid system:

Our data indicate lasting consequences in social behavior and pain sensitivity following peer-rejection in adolescent female rats. These behavioral impairments are accompanied by persistent alterations in CB1R signaling.

CB1 is the endocannabinoid receptor found mainly in the brain and central nervous system!

Yes, it's shown to have powerful anti-anxiety effects but social anxiety is very specific.

Here, we're going to geek out.

Another study took a look at what was going on in the brain for anxiety and threat response when seeing fearful faces (very pertinent to social anxiety).

We'll decipher this as we go along but hold on to your hats…

In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit.

So they used statistical analysis of brain scans to show that a circuit lit up during the experiment between two brain areas.

The amygdala (fear center) and the anterior cingulate (the pregenual ACC is part of this).

Those two areas should be very familiar from everything we discussed above.

Remember the circuit we discussed above that was very important to social anxiety?

Too much fear response and then the rational brain would ramp up the signal instead of calming it down??

Now watch what happens with CBD on this circuit.

CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces.

As a wrap-up…

This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.

It literally unwinds our tightly packed DNA to expose regions to more expression!

The researchers don't even know what to make of this.

The point is this...serotonin is incredibly powerful and if we look at the diverse list of potential side effects, directly hammering the levels of it will likely seem like using leeches some day in the future.

We apologize if we're a bit jaded but it's from our experience.

Most doctors will tell you to take a benzo for the first two weeks so that the SSRI can ramp up.

At best, that's misguided.

What they're not telling you (or don't know) is that there can actually be an increase in anxiety and depression as a result of SSRI use for the first two weeks.

The benzo is just to mask that feeling.

Why on earth would an increase in serotonin cause an increase of anxiety and depression initially?

We'll assume that you actually have too low a level of serotonin (which a doctor can't even test for).

They just assume you do.

That's why some people get serotonin syndrome (too much serotonin) which is potentially fatal.

Remember...serotonin is not just a mood stabilizer.

It's a brain signalling workhorse between neurons, between brain areas, between body and brain, and even with the DNA within neurons itself (brand spanking new research).

Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate—making them one of the few known examples of neurons in the brain that release two different chemicals.

Glutamate! One of the key "gas pedals" in the brain that has a direct effect on anxiety (see anxiety summary here).

That will come back around below with CBD.

Moreover…

Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert.

This speaks to the HP1 and HP2 differences above but also to how serotonin can create different...even opposite results...depending on what area of the brain you're boosting!

We could geek out all day on this but we'll save for a separate article.

We have to get to CBD eventually, right??

The other classes of anti-anxiety meds

The other various off-shoots are really just more of the same two above.

The older triciclates also attempt to make more serotonin available

They include:

Amitriptyline

Imipramine

nortriptyline

These have largely been replaced by the SSRI's above as they have more serious issues.

SNRI's work on both the Serotonin and Norepinephrine systems.

They are similar to SSRI's in that they make more of each available to neurons.

The SSRI's by far dominate what is prescribed for anxiety.

Another medication, BuSpar is also used for anxiety.

It works to boost serotonin and dopamine activity in the brain.

The issue with BuSpar is whether it's effective for anxiety and it's rarely prescribed by itself.

However, a double-blind placebo-controlled study of 30 patients with SAD in 1997 showed no improvement compared to placebo.

Recent studies have shown that hydroxyzine's main effect is on histamine with very weak effects on serotonin, dopamine, and acetylcholine (the dementia tie above):

Unlike many other first-generation antihistamines, hydroxyzine has very low affinity for the muscarinic acetylcholine receptors, and in accordance, has low or no propensity for producing anticholinergic side effects

Immune system - inflammatory response as well as cell growth/death cycles

Let's start with the neurotransmitters.

CBD and GABA, Glutamate, and Serotonin

GABA is such a better proxy for anxiety than Serotonin.

It's more direct in its action and activity in the anxiety circuit.

What does CBD do there?

It was shown to directly increase GABA signalling:

The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current, more than twice the potentiation seen with other α-subunit receptor combinations

The fact that modulation of GABAA receptors by 2-AG is exclusively observed at low concentrations of GABA may be the reason why we were not able to establish conditions to measure robust effects of 2-AG in brain slice experiments.

Here's a pretty good explanation of the glutamate pathway with our endocannabinoids:

Upon activation by 2-AG and Anandamide, CB1 drives cellular cascades that block the flow of calcium into the presynaptic terminal. This then causes a significant reduction on glutamate release, downregulating the activity of glutamate on the postsynaptic neuron.

Again, SSRI's have been shown to have a similar effect and countering the ravishes of brain stress may be the real positive for anxiety and depression.

We just don't want the nasty side effect.

Speaking of stress response….

Remember that chemical CFR from above (we won't blame you if you don't!)

It's the chemical messenger between our brain and the stress response organs.

Stay with us...this gets very cool and no one is really talking about it.

Remember how SSRI's initially increase anxiety and depression?

The reason is that serotonin is a general messenger across many pathways.

One of them is this CFR pathway.

Boost CFR = feel anxiety

It's that simple.

What does this have to do with CBD?

If you boost CFR, it increases an endocannabinoid called FAAH which eats up Anandamide in the Amygdala (our fear and emotional center of the brain -very important to anxiety, addiction, and other issues).

It's really difficult to get good stats on probability of this result.

The only stat we could find was just under 10,000 official diagnosis back in 2004 but the number of prescriptions have skyrocketed since then and it's very difficult to test for it.

Insult to injury...guess what is usually used to address Serotonin syndrome..

You guessed it...Benzos!

Benzos are used to mask the anxiety/depression of new SSRI's and they're used on the back end if the SSRI's cause serotonin sydrome.

For now, that leaves us with the standard side effect of any given SSRI and there's quite a bit there.

Always work with your doctor but weaning slowly is recommended with SSRI's

Are SSRI's even effect for anxiety?

As we mentioned, serotonin is more targeted to depression.

New studies are not looking great.

the analysis showed a difference between treatment with an antidepressant and treatment with a placebo of 4.0 points on the Hamilton Anxiety Rating Scale for patients with severe GAD. For patients with mild GAD, the antidepressant-placebo difference was just 1.4 points.

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https://indigonaturals.net/blogs/news/what-is-the-best-cbd-for-anxiety2019-03-13T22:26:00-07:002019-03-24T18:46:48-07:00What is the Best CBD for Anxiety?Indigo Naturals
What is the Best CBD for Anxiety?

The goal is to avoid all the bad CBD out there especially for allergy sufferers

In fact, anxiety is the leading reason for people to try and stay with CBD.

Again..it's a 4000+ word total review of CBD for anxiety so we'll leave the studies and research (we reference over a dozen) there but CBD might be the best tool we have now for anxiety with a very strong safety profile.

We get into the meds as well.

Once we establish that CBD has potential to help, how do we find the best CBD for anxiety?

Let's start with the basics.

Minimum requirements of CBD for anxiety

There are some minimum requirements that apply...especially for anxiety!

The CBD must be sourced from organically grown industrial hemp in the US

The CBD should be Isolate only (we'll get into why below)

The CBD must be CO2 extracted - much cleaner process

The CBD must be 3rd party tested for the following items

THC free - very important as THC can actually increase anxiety

Solvent free - solvents can cause an immune response which may make anxiety worse

Pesticide free - same effect on the immune system

Bacteria and mold free - we want to feel better...not worse

We make sure to put our 3rd party results at the bottom of every page on this site.

It's amazing how many bogus brands out there don't even run testing!

CBD products are not FDA regulated so it's incredibly important to have 3rd party testing and it should be readily available.

Let's look at each of these with a little more detail.

The CBD must come from the US!

There are so many bad products out there coming from China and Mexico.

Who knows what is in there but if the recent recalls of blood pressure meds (heavily regulated by the FDA) for carcinogens is any indication, CBD must be US sourced.

Organically grown goes to the fact that hemp is very good at removing things from the ground.

They call it a soil remediator for a reason!

The solvent, pesticide, bacteria, and mold should be pretty obvious.

We don't want these substances in anything we might put in our body but it's even more important for anxiety.

Most of the new research is pointing to immune response and inflammation causing a host of mental health issues.

Or at least, making them worse!

Inflammation in the brain and central nervous system IS anxiety.

Along with a host of other issues.

This needs to be 3rd party tested and out of our CBD.

We're amazed when we research brands for people on reddit and the given brand has testing but it shows a nasty pesticide out of range!

Best CBD for anxiety without THC

At IndigoNaturals, we literally designed our CBD approach based on our initial trial and error start for anxiety.

We went through all the full spectrum issues.

We learned about the basic safety requirements that are a must

We found out what levels of CBD matter for anxiety

Maybe more importantly, we realized that we actually need to afford this!

Look, every indication is that with the right CBD, you're going to see relief for anxiety.

We say this because we see it daily.

It might be the single greatest driver behind CBD's popularity (with pain and sleep close behind).

The research on anxiety is much more established for CBD.

So how do we get the best value CBD for anxiety?

This all comes down to cost per mg of CBD!

That's the golden rule of CBD.

We specifically priced our CBD at 4-5 cents per mg of CBD to be among the best priced options on the market.

Why?

When really big companies are charging 2, 3, even 4 times that amount for the same product (actually full spectrum which can make anxiety worse and is cheaper to make)...

Because of 2017.

That's the year one of our founders was reeling from anxiety caused by hormones plummeting during perimenopause.

You can read the full story here but there was a 3 day window with no sleep (from Lexapro) where things were very bleak.

That's was the driving force for our pricing.

Don't take advantage of people suffering seems like a pretty basic prerequisite.

We could charge more and still be under the market but people are suffering.

If you've been there personally, you understand.

We've been there. We got out. Now, it's your turn.

Everyone deserves to feel better.

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https://indigonaturals.net/blogs/news/whats-the-best-way-to-take-cbd-for-anxiety2019-03-12T18:03:00-07:002019-03-24T18:47:58-07:00What's the Best Way To Take CBD for Anxiety?Indigo Naturals
What's the Best Way To Take CBD for Anxiety?

Just to round it out, testosterone has a powerful anxi-anxiety effect as well.

This may get to the heart of why women have an 85% higher risk for anxiety than men.

Testosterone is an androgen, or a hormone that drives masculine traits.

Women have testosterone as well but estrogen is dominant can can reduce testosterone levels.

As for testosterone's effect on GABA…

testosterone metabolites, androstanediol and androsterone, have little or no affinity for androgen receptors (11), but they are potent GABAA (gama aminobutyric acid A) receptor agonists and have GABA-mediated functions

Biomarkers of inflammation, including inflammatory cytokines and the acute-phase reactant C-reactive protein (CRP), are reliably increased in a subset of patients with depression, anxiety disorders and post-traumatic stress disorder (PTSD).

Remember that brain area that's the seat of fear, anxiousness, and emotional context...the Amygdala:

Administration of innate immune stimuli to laboratory subjects and the associated release of inflammatory cytokines has been shown to affect brain regions involved in fear, anxiety and emotional processing such as the amygdala.

Keep in mind that a 20-60% of our gut bacteria have never been cultured!

Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA

They even found bacteria that appeared to reduce or "eat" GABA and other neurotransmitters:

By coupling 16S ribosomal RNA sequencing with functional magnetic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression.

Three specific endocannabinoids (cannabinoids that we naturally make in our bodies) appears to be critical to anxiety:

Anandamide (AEA) - appears to reduce anxiety

FAAH - elevated levels appear to increase anxiety

2-AG - appears to reduce anxiety

Remember that the goal of the endocannabinoid system is balance.

You need anxious feelings sometimes!

Like if the proverbial tiger jumps out of the bush or you're acting in a risky way.

It's there to protect you.

That requires a TEMPORARY imbalance to elicit that effect.

It's when the imbalance is long term or not due to any threatening issue that we have a problem.

Stress in excitatory. It boosts glutamate which eats up GABA.

Long term stress can exhaust this and create anxiety.

The three endocannabinoids are trying to balance out this system.

There's a slew of research on how endocannabinoid systems govern this but a few studies...

First, FAAH.

A plethora of studies involving pharmacological blockade of FAAH by the specific inhibitor URB597 demonstrated anxiolytic behaviours in a variety of species using different anxiety paradigms

They used a specific chemical to block FAAH from working which reduced anxiety.

Next, Anandamide (the so-called "bliss" molecule)

The effects of diazepam (benzo) was increased with the addition of Anandamide:

These results suggest a possible synergistic action on glutamatergic inhibition (by increase in AEA) and GABAergic enhancement (by the activation of GABA A receptors).

This basically means that Anandamide appeared to take the foot off the gas (glutamate) in the brain and boost GABA at the same time (apply the break).

Next, 2-AG

2-AG was proposed as the endocannabinoid responsible for the tonic inhibition of excitatory neurotransmission, and interaction with the inhibitory network was excluded using GABA A and GABA B receptor antagonists

2-AG appeared to calm the excitability in the brain and boost the GABA networks.